Kirigami-inspired stents for sustained local delivery of therapeutics

ABSTRACT

The present disclosure provides a kirigami-inspired injectable stent system. The stent systems and methods enable radial/circumferential and longitudinal delivery of an extended release of therapeutics within tubular structures of the body, such as the GI tract and trachea. According to some aspects, a kirigami-based injectable stent system is provided that can enable drug release through deposition of therapeutic-coated needles of the stent in the tubular mucosa, such as often found in the gastrointestinal tract or trachea.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is based on, claims priority to, andincorporates herein by reference in its entirety, U.S. ProvisionalPatent Application No. 63/041,154 filed Jun. 19, 2020, entitled“Kirigami-inspired Stents for Sustained Local Delivery of Therapeutics.”

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under Grant No. R01EB000244 awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

BACKGROUND

Implantable drug depots have been applied for decades across a range ofsites in the body, including the brain. For tubular structures in thebody, coated stents have been applied to provide local highconcentrations of a therapeutic, as found in drug eluting stents. In thegastrointestinal (“GI”) tract, coated stents have been explored, thoughsuffer from a significant rate of complications including stentmigration and tissue perforation. Moreover, the delivery of therapeuticsfrom drug eluting stents is governed by diffusion limitations throughtissue, potentially limiting delivery to therapeutics of lower molecularweight and particular physico-chemical characteristics which supportpartitioning of the drug into the mucosa.

In the GI tract, endoscopic injection, initially pioneered through thedevelopment of the Carr-Locke Needle, transformed the capacity tolocally deliver therapeutics for a range of applications includinghemostasis with epinephrine, sclerosant injection for variceal ablation,submucosal lifts with normal saline and other materials, as well assteroid injections for inflammation control, and injection of biologicsfor inflammatory stricture management. All of these applications apply ahypodermic needle, which can be deployed endoscopically supportingsingle site injection.

SUMMARY

Recognizing that many GI pathologies, including inflammatory boweldisease, eosinophilic GI disorders, and Celiac disease, affect extendedmulti-centimeter segments of the GI tract, the present disclosureprovides a solution for rapid circumferential submucosal deposition ofcontrolled drug releasing systems.

Implantable drug depots have the capacity to locally meet therapeuticrequirements by maximizing local drug efficacy and minimize potentialsystemic side effects. The GI tract represents a site with a broad rangeof pathology affecting its tubular structure. Its length and tubularstructure though make the application and deposition of drug depotschallenging as current injectable systems, as briefly described above,generally only facilitate single point administration.

According to aspects of the present disclosure, a kirigami-mediatedinjectable stent system is provided. The systems and methods describedherein enable radial/circumferential and longitudinal intramucosaldelivery for an extended release of therapeutics within tubularstructures of the body. According to some aspects, a kirigami-basedinjectable stent system is provided that can enable ultra-long localdrug release through deposition of drug-loaded polymeric particles inthe tubular mucosa of the GI tract.

According to some aspects of the present disclosure, a stent fortreating tissue within a gastrointestinal tract or trachea of a subjectis provided. The stent includes a tubular body extending along a centralaxis and configured to move between a retracted position and anelongated position, and a plurality of projections formed into thetubular body, each projection configured to form a cutting edge topierce a submucosal tissue within the gastrointestinal tract or trachea.Each projection among the plurality of projections is configured toundergo a change in orientation relative to the central axis when thetubular body moves between the retracted position and the elongatedposition.

According to some aspects of the present disclosure, a stent system fortreating a tissue within a gastrointestinal tract or trachea of asubject is provided. The system includes a tubular body extending alonga central axis to form a lumen within the tubular body an actuatorreceived within the lumen and configured to move the tubular bodybetween a retracted position and an elongated position, and a pattern ofa plurality of cuts formed along the tubular body and extending throughthe tubular body to the lumen. The pattern of the plurality of cutsdeploys into a plurality of interconnected projections that areconfigured to extend radially away from the tubular body relative to thecentral axis to engage a submucosal tissue within the gastrointestinaltract or trachea of a subject when the tubular body is moved towards theelongated position.

According to some aspects of the present disclosure, a method ofinserting a stent into a gastrointestinal tract or trachea a subject isprovided. The method includes positioning a stent to a target tissuesite within a gastrointestinal tract or trachea, the stent having atubular body extending along a central axis to form a lumen within thetubular body, and pressurizing an actuator received within the lumen tomove the tubular body from a retracted position to an elongatedposition. A surface of the tubular body includes a pattern of aplurality of cuts configured to deploy into a plurality ofinterconnected projections as the tubular body is moved into theelongated position to engage the target tissue site of the subject.

The foregoing and other aspects and advantages of the disclosure willappear from the following description. In the description, reference ismade to the accompanying drawings which form a part hereof, and in whichthere is shown by way of illustration a preferred configuration of thedisclosure. Such configuration does not necessarily represent the fullscope of the disclosure, however, and reference is made therefore to theclaims and herein for interpreting the scope of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood and features, aspects andadvantages other than those set forth above will become apparent whenconsideration is given to the following detailed description thereof.Such detailed description makes reference to the following drawings.

FIG. 1 illustrates a perspective view of a kirigami-inspired stent in anextended position according to one aspect of the present disclosure.

FIG. 2 illustrates a perspective view, including a cut-away, of thekirigami-inspired stent of FIG. 1 in a retracted position.

FIG. 3 illustrates a perspective detail view of denticle-like projectionelements of the kirigami-inspired stent of FIG. 1 in a deployedposition.

FIG. 4 illustrates a plan view of a pattern of cuts forming thedenticle-like projection elements of the kirigami-inspired stent of FIG.2 in a stowed position.

FIG. 5 illustrates a perspective exploded view of an actuator for thekirigami-inspired stent of FIG. 2.

FIG. 6 illustrates a perspective detailed view of a fiber reinforcementfor the actuator of FIG. 5.

FIG. 7 illustrates a perspective view of another non-limiting example ofa kirigami-inspired stent in an extended position according to anotheraspect of the present disclosure.

FIG. 8 illustrates a schematic of a penetration depth of a projectionelement of the kirigami-inspired stents.

FIG. 9 illustrates a schematic of an exemplary cut forming theprojection elements of the kirigami-inspired stent of FIG. 1.

FIG. 10 illustrates a schematic of an exemplary cut forming theprojection elements akin to the kirigami-inspired stent of FIG. 7.

FIG. 11 illustrates a schematic of another exemplary cut forming theprojection elements akin to the kirigami-inspired stent of FIG. 7.

FIG. 12 illustrates a schematic of yet another exemplary cut forming theprojection elements akin to the kirigami-inspired stent of FIG. 7.

FIG. 13 illustrates a perspective view of another non-limiting exampleof a kirigami-inspired stent in a retracted position according toanother aspect of the present disclosure.

FIG. 14 illustrates a schematic of the projection elements of thekirigami-inspired stent of FIG. 13 including etched striations accordingto one aspect of the present disclosure.

FIG. 15 illustrates an exemplary method of loading a therapeutic agentonto a kirigami-inspired stent to produce a drug eluting stent.

FIG. 16 illustrates a flow diagram of a method of inserting and removinga kirigami-inspired stent according to one aspect of the presentdisclosure.

FIG. 17 illustrates an exemplary schematic of a kirigami-inspired stentinserted into different portions of a subject's GI tract.

FIG. 18 illustrates an exemplary schematic of a kirigami-inspired stentinserted into a subject's trachea.

FIG. 19 illustrates a perspective view of a molding process for making acast or injection molded actuator body.

FIG. 20 illustrates a perspective view of the cast or injection moldedactuator body of FIG. 19 out of the mold.

FIG. 21 illustrates a perspective view of the cast or injection moldedactuator body of FIG. 20 with a fiber reinforcement wrapping.

FIG. 22 illustrates a perspective view of a cutting process for makingan outer shell of a kirigami-inspired spent and a photograph of theresult of the cutting process.

FIG. 23 illustrates a flow diagram of a surface treatment process forthe outer shell of FIG. 22 and a photograph of the result of the surfacetreatment process.

FIG. 24 illustrates a perspective view of the outer shell of FIG. 22 inan assembled state in preparation for receiving an actuator.

FIG. 25 illustrates nominal stress-strain curves for a tensile testcharacterizing a material for kirigami-inspired stents.

FIG. 26 illustrates a perspective view of an exemplary dogbone for atensile test of a material for an actuator for a kirigami-inspiredstents.

FIG. 27 illustrates an experimental setup for the tensile test for theactuator material.

FIG. 28 illustrates nominal stress-strain curves for the tensile testcharacterizing the material for the actuator for the kirigami-inspiredstents.

FIG. 29 illustrates the radial strain and needle angle as a function ofactuator pressure for a kirigami-inspired stent.

FIG. 30 illustrates a map of the effect of needle length and stentthickness on maximum actuator pressure.

FIG. 31 illustrates a map of the effect of needle length and stentthickness on maximum axial strain.

FIG. 32 illustrates a map of the effect of needle length and stentthickness on maximum radial strain.

FIG. 33 illustrates a map of the effect of needle length and stentthickness on maximum needle angle.

FIG. 34 illustrates an experimental setup for a stiffness test ofneedles of a kirigami-inspired stent in the normal direction.

FIG. 35 illustrates the results of the stiffness test of FIG. 34.

FIG. 36 illustrates an experimental setup for a uniaxial tensile test ofa kirigami-inspired stent.

FIG. 37 illustrates experimental images showing undeformed and buckledconfigurations of a kirigami-inspired stent under different levels ofapplied strain.

FIG. 38 illustrates nominal stress-strain curves of kirigami-inspiredstents with various thicknesses.

FIG. 39 illustrates numerical and experimental images of akirigami-inspired stent at different levels of actuator pressure.

FIG. 40 illustrates numerical and experimental results of axial strainas a function of actuator pressure.

FIG. 41 illustrates numerical and experimental results of radial strainas a function of actuator pressure.

FIG. 42 illustrates numerical and experimental results of needle angleas a function of actuator pressure.

FIG. 43 illustrates kirigami-inspired stents with various needlelengths.

FIG. 44 illustrates experimental results of controlling needlepenetration depth using protrusions along edges of a needle of akirigami-inspired stent.

FIG. 45 illustrates a 3D micro-CT image of a deployed kirigami-inspiredstent with 2D cross-sectional slices.

FIG. 46 illustrates histological image analysis performed in esophagealtissues at needle penetration sites.

FIG. 47 illustrates images of an exemplary spray coating apparatus toapply coatings onto a kirigami-inspired stent.

FIG. 48 illustrates a 2D epi-fluorescence image of needle penetrationsites.

FIG. 49 illustrates an image of penetration sites.

FIG. 50 illustrates histological image analysis performed in tissues ofa trachea at needle penetration sites.

FIG. 51 illustrates images of an exemplary method of continuousmicrofluidic drug-PLGA droplet generation.

FIG. 52 illustrates morphological characteristics of synthesized drugparticles.

FIG. 53 illustrates drug loading and encapsulation efficacy parameters.

FIG. 54 illustrates a release profile of encapsulated budesonide.

FIG. 55 illustrates images of coated kirigami-inspired stents and amagnified view of a needle surface/tip taken by a fluorescencemicroscope.

FIG. 56 illustrates a graph of concentrations of budesonide deliveredusing a kirigami-inspired stent.

DETAILED DESCRIPTION

Before any aspects of the invention are explained in detail, it is to beunderstood that the invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description or illustrated in the following drawings. Theinvention is capable of other aspects and of being practiced or of beingcarried out in various ways. Also, it is to be understood that thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having” and variations thereof herein ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items. Unless specified or limited otherwise, theterms “mounted,” “connected,” “supported,” and “coupled” and variationsthereof are used broadly and encompass both direct and indirectmountings, connections, supports, and couplings. Further, “connected”and “coupled” are not restricted to physical or mechanical connectionsor couplings.

The use herein of the term “axial” and variations thereof refers to adirection that extends generally along an axis of symmetry, a centralaxis, an axis of rotation, or an elongate direction of a particularcomponent or system. For example, axially extending features of acomponent may be features that extend generally along a direction thatis parallel to an axis of symmetry or an elongate direction of thatcomponent. Further, for example, axially aligned components may beconfigured so that their axes of rotation are aligned. Similarly, theuse herein of the term “radial” and variations thereof refers todirections that are generally perpendicular to a corresponding axialdirection. For example, a radially extending structure of a componentmay generally extend at least partly along a direction that isperpendicular to a longitudinal or central axis of that component. Theuse herein of the term “circumferential” and variations thereof refersto a direction that extends generally around a circumference of anobject or around an axis of symmetry, an axis of rotation, a centralaxis, or an elongate direction of a particular component or system.

As also used herein, unless specified or limited otherwise, the terms“approximately” and “substantially” and variations thereof, when usedrelative to a numerical value, define a range of values within 20% ofthe numerical value (e.g., within 15%, 10%, or within 5%).

In some implementations, devices or systems disclosed herein can beutilized, manufactured, or treated using methods embodying aspects ofthe invention. Correspondingly, any description herein of particularfeatures, capabilities, or intended purposes of a device or system isgenerally intended to include disclosure of a method of using suchdevices for the intended purposes, of a method of otherwise implementingsuch capabilities, of a method of manufacturing relevant components ofsuch a device or system (or the device or system as a whole), and of amethod of installing or utilizing disclosed (or otherwise known)components to support such purposes or capabilities. Similarly, unlessotherwise indicated or limited, discussion herein of any method ofmanufacturing or using for a particular device or system, includinginstalling the device or system, is intended to inherently includedisclosure, as embodiments of the invention, of the utilized featuresand implemented capabilities of such device or system.

The following discussion is presented to enable a person skilled in theart to make and use embodiments of the invention. Various modificationsto the illustrated embodiments will be readily apparent to those skilledin the art, and the generic principles herein can be applied to otherembodiments and applications without departing from embodiments of theinvention. Thus, embodiments of the invention are not intended to belimited to embodiments shown, but are to be accorded the widest scopeconsistent with the principles and features disclosed herein. Thefollowing detailed description is to be read with reference to thefigures, in which like elements in different figures have like referencenumerals. The figures, which are not necessarily to scale, depictselected embodiments and are not intended to limit the scope ofembodiments of the invention. Skilled artisans will recognize theexamples provided herein have many useful alternatives and fall withinthe scope of embodiments of the invention.

Kirigami is a Japanese form of paper art similar to origami thatincludes cutting of the paper and can enable the design of a range offunctional tools and programmable systems from macroscale soft actuatorsand robots to microelectronics and nanostructures. Buckling-inducedkirigami structures are engineered to utilize local elasticinstabilities for versatile shape transformation from flat, generallysmooth surfaces to complex three-dimensional architectures. According tosome applications, the buckling kirigami metasurfaces have been appliedto footwear outsoles to generate higher friction forces and mitigate therisk of slips and falls in a range of environments.

As explained herein, inspired from the skin of scaly-skin animals likesnakes and sharks, an injectable stent was developed which is composedof a periodic array of denticle-like needles (e.g., a kirigamicylindrical shell) integrated with a linear actuator (e.g., a pneumaticsoft actuator). As detailed herein, a combination of finite element(“FE”) simulations and experiments, kirigami shells and linear actuatorswere identified to develop injectable stents in multiple length scalesthat can be easily deployed in the tubular lumen of the GI tract such asesophagus as well as arteries and airways. By pressurizing the softactuator, the kirigami needles buckle out (e.g., extend) such that theresulting needles provide required stiffness and radial expansion (insome examples, up to 60% of the stent diameter) to enable injections ofdrug-loaded particles into the tissue of a subject (e.g., intosubmucosal tissues of the GI tract). These kirigami-based injectablestents serve as a class of drug-eluting stents, capable of releasingdrug depots through multi-point deposition of drug particles, therebyenhancing sustained local delivery of therapeutics.

KIRIGAMI-INSPIRED STENT EXAMPLES

Referring to FIGS. 1 and 2, one non-limiting example of a stent 10 isillustrated. The stent 10 can define a tubular body 12 extending axiallyalong a central axis 14 and configured for insertion into the GI tractor trachea. The tubular body 12 of the stent 10 is configured to undergoa shape change in at least one dimension. In the illustratednon-limiting example, the tubular body 12 is axially extendable betweena first, retracted position (FIG. 2) and a second, extended position(FIG. 1). In the extended position, the tubular body 12 is elongated inthe axial direction relative to the retracted position. As will bedescribed, the elongation of the tubular body 12 between the retractedposition and the extended position is configured to deploy projectionsconfigured to pierce or engage tissue of a subject.

The tubular body 12 can include a cylindrical outer shell 16 forming alumen 17 (e.g., a hollow core) and an actuator 18 arranged within thelumen 17 of the outer shell 16. The outer shell 16 can include at leastone cut 20. In the illustrated non-limiting example, the outer shell 16can include a patterned array of a plurality of interconnected cuts 20(e.g., openings). In the illustrated non-limiting example, the pluralityof cuts 20 extend along at least a portion of the axial length of thetubular body 12. For example, the plurality of cuts 20 can extend alongat least 50% of an entire length L₀ of the tubular body 12. According tosome non-limiting examples, the plurality of cuts 20 can extend alongbetween about 50% and about 100% of the entire length L₀ of the tubularbody 12. According to the illustrated non-limiting example, theplurality of cuts 20 can extend along between about 80% and about 95% ofthe entire length L₀ of the tubular body 12. In the illustratednon-limiting example, the plurality of cuts 20 extend along at least aportion of the circumference of the tubular body 12. For example, theplurality of cuts 20 can extend along at least 50% of the circumferenceof the tubular body 12. According to some non-limiting examples, theplurality of cuts 20 can extend along between about 50% and about 100%of the circumference of the tubular body 12. According to theillustrated non-limiting example, the plurality of cuts 20 can extendalong between about 90% and about 100% of the circumference of thetubular body 12.

The length L₀ of the tubular body 12 can be defined as an initial lengthbetween a first end 21 and an opposing send end 23 of the tubular body12 when the tubular body 12 is in the retracted position (FIG. 2).According to some non-limiting examples, the length L₀ can be betweenabout 0.1 cm and about 40 cm. According to other non-limiting examples,the length L₀ can be between about 1 cm and about 20 cm. According toyet further non-limiting examples, the length L₀ can be between about 1cm and about 15 cm. According to the illustrated non-limiting example,the length L₀ is about 8 cm.

The tubular body 12 can also define a nominal outer diameter D, definedas an initial diameter of the outer shell 16 when the tubular body 12 isin the retracted position (FIG. 2). According to some non-limitingexamples, the diameter D can be between about 1 mm and about 100 mm.According to other non-limiting examples, the diameter D can be betweenabout 1 mm and about 50 mm. According to yet further non-limitingexamples, the diameter D can be between about 1 mm and about 25 mm.According to the illustrated non-limiting example, the diameter D isabout 12.5 mm.

When the tubular body 12 is elongated from the retracted position to theextended position, the tubular body 12 can define an elongated lengthL_(E) (FIG. 1) that is greater relative to the initial length L₀.According to some non-limiting examples, the elongated length L_(E) canbe between about 1% and about 100% greater than the initial length L₀.According to other non-limiting examples, the elongated length L_(E) canbe between about 10% and about 80% greater than the initial length L₀.According to yet further non-limiting examples, the elongated lengthL_(E) can be between about 15% and about 40% greater than the initiallength L₀. According to the illustrated non-limiting example, theelongated length L_(E) is about 30% greater than the initial length L₀.

The plurality of cuts 20 can be configured to form a kirigami-inspiredpattern configured to undergo a shape change when stress is axiallyapplied along the outer shell 16. via the actuator 18. The at least onecut 20 can form at least one projection element 22. In the illustratednon-limiting example, the series of patterned cuts 20 can form aplurality of projection elements 22 (e.g., needles). When the tubularbody 12 of the stent 10 is in a retracted position (FIG. 2), theprojection elements 22 are substantially planar with the outer shell 16and undeformed. When the tubular body 12 of the stent 10 is elongated(e.g., via the actuator 18) from the retracted position towards theextended position (FIG. 1), the projection elements 22 become deformedand deploy to extend radially outward from the outer shell (e.g.,relative to the central axis 14).

For example, as will be described, the outer shell 16 can be configuredto automatically respond to strain applied in a direction along thecentral axis 14. That is, the series of patterned cuts 20 form a surfaceon the outer shell 16 that buckles in response to applied axial strainto form a plurality of projection elements from that cut surface. In theillustrated non-limiting examples, the actuator 18 is configured toapply the axial strain, and that axial strain results in stress withinthe outer shell 16 that causes the projection elements 22 to extendoutwards from an orientation in which the projection elements form asubstantially uniform (e.g., flat) cylindrical surface, into anorientation in which the projection elements deploy radially outwardsrelative to the central axis 14. According to some non-limitingexamples, the magnitude of applied axial strain to the outer shell 16can correspond to a magnitude of radial extension of the projectionelements 22. That is, owing to the pattern of cuts 20 formed in theouter shell 16, a surface is provided that transforms in a radialdirection in response to strain applied in an axial direction.

Referring now to FIGS. 3 and 4, with the tubular body 12 in an extendedposition, the projection elements 22 can deploy from an undeformed state(FIG. 4) to a deformed state (FIG. 3). In a deformed state, theprojection elements 22 form denticle-like needles. In the illustratednon-limiting example, the projection elements 22 define a convexthree-dimensional surface forming a barb shaped needle. The projectionelements 22, when deployed to the deformed state, reveal a plurality ofopenings 24 in the outer shell 16. The plurality of openings 24 extendthrough the outer shell 16 and into the lumen 17.

With particular reference to FIG. 3, with the projection elements 22 ina deployed position (with the tubular body 12 in the extended position),the protruding projection elements 22 can provide radial expansion up to80% of the stent diameter (e.g., up to 60%, 40%, etc.). In theillustrated non-limiting example, the projection elements 22 can definea needle angle θ. The needle angle θ can be defined as the angle of asurface 26 of the projection element 22, formed between a base 28 and aneedle tip 30, relative to the central axis 14 of the tubular body.According to some non-limiting examples, the projection elements 22 candefine a needle angle θ between about 0 degrees and about 90 degrees.According to other non-limiting examples, the projection elements 22 candefine a needle angle θ between about 5 degrees and about 60 degrees.According to yet further non-limiting examples, the projection elements22 can define a needle angle θ between about 10 degrees and about 40degrees. According to the illustrated non-limiting example, theprojection elements 22 define a needle angle θ of about 20 degrees.

Referring now to FIG. 4, illustrating the projection elements 22 in anundeformed state (e.g., in a stowed state, with the tubular body in theretracted position), the cuts 20 can be configured as a pattern ofdenticle-like cuts. For example, each individual projection element 22among the plurality of projection elements 22 formed by the pattern ofcuts 20 can define a triangular shaped cutting edge, with first andsecond edges 32, 34 of the triangular shape being formed by a continuouscut 20, and the base 28 (illustrated in FIG. 4 as a broken line) beingformed by an uncut portion. In the illustrated non-limiting, theprojection elements 22 define a circular triangle. That is, the firstand second edges 32, 34 of each projection element 22 define an arcuateshape. In the illustrated embodiment, the first and second edges 32, 34of the projection element 22 define a convex arcuate shape. The arcuateshape of the first and second edges 32, 34 can define a radius ofcurvature between being a straight line and about a 100 mm radius.According to some non-limiting examples, the radius of curvature can bebetween about 1 mm and about 60 mm. According to other non-limitingexamples, the radius of curvature can be between about 1 mm and about 40mm. According to yet further non-limiting examples, the radius ofcurvature can be between about 1 mm and about 20 mm. According to theillustrated non-limiting example, the radius of curvature is about 10mm.

The patterned cuts 20 forming the projection elements 22 can becharacterized by a needle length l, hinge length δ, and cut angle γ. Theneedle length l can be described as a characteristic length of thepatterned cut 20 and can be considered as a length of the needle formedby the projection element 22. The needle length l can be defined by adistance between the needle tip 30 of the projection element 22 andeither one of a first distal end 36 of the first edge 32 or a seconddistal end 38 of the second edge 34 (i.e., distal ends of the cut 20).According to some non-limiting examples, the projection elements 22 candefine a needle length l between about 0.1 mm and about 60 mm. Accordingto other non-limiting examples, the projection elements 22 can define aneedle length l between about 1 mm and about 30 mm. According to yetfurther non-limiting examples, the projection elements 22 can define aneedle length l between about 1 mm and about 15 mm. According to theillustrated non-limiting example, the projection elements 22 define aneedle length l of about 10 mm.

The hinge length δ can be described as the width of ligaments forming aninterstitial spacing separating adjacent cuts 20. The hinge length δ canbe defined by a distance between the needle tip 30 of a first projectionelement 22 a and either one of the first distal end 36 or the seconddistal end 38 of a second, adjacent projection element 22 b. Accordingto some non-limiting examples, the cuts 20 can define a hinge length δbetween about 0.1 mm and about 10 mm. According to other non-limitingexamples, the cuts 20 can define a hinge length δ between about 0.1 mmand about 5 mm. According to yet further non-limiting examples, the cuts20 can define a hinge length δ between about 0.1 mm and about 2 mm.

The cut angle γ can be described as the angle of the cut 20 formingeither one of the first and second edges 32, 34 of the projectionelement 22 relative to a plane 25 intersecting and orthogonal to thecentral axis 14. According to some non-limiting examples, the cuts 20can define a cut angle γ between about 0 degrees and about 90 degrees.According to other non-limiting examples, the cuts 20 can define a cutangle γ between about 5 degrees and about 45 degrees. According to yetfurther non-limiting examples, the cuts 20 can define a cut angle γbetween about 10 degrees and about 45 degrees. According to theillustrated non-limiting example, the cuts 20 define a cut angle γ ofabout 30 degrees.

Referring still to FIG. 4, a dimensionless ratio δ/l can be defined fora given pattern of cuts 20, the dimensionless ratio δ/l can correlate toa magnitude of pop-out deformation (e.g., a magnitude of needle angle θ,a magnitude of convex surface deformation in the projection elements 22,etc.) upon elongation of the tubular body 12. According to somenon-limiting examples, the cuts 20 can define a dimensionless ratio δ/lbetween 0 and 1. According to other non-limiting examples, the cuts 20can define a dimensionless ratio δ/l between 0 and about 0.5. Accordingto yet further non-limiting examples, the cuts 20 can define adimensionless ratio δ/l between 0 and about 0.2. According to theillustrated non-limiting example, the cuts 20 define a dimensionlessratio δ/l of about 0.13.

The cuts 20 forming the projection elements 22 can be evenly (e.g.,periodically) circumferentially spaced around the outer shell 16 (see,e.g., FIG. 1). According to the illustrated non-limiting example, aplurality of rows of circumferentially spaced cuts 20 are arranged alongthe axial length of the outer shell 16. As best illustrated in FIG. 4, afirst row 40 a of circumferentially spaced cuts 20 can be rotationallyoffset from a second, adjacent row 40 b of circumferentially spaced cuts20. In the illustrated non-limiting example, the rotational offsetbetween adjacent rows 40 a, 40 b of circumferentially spaced cuts 20 canbe such that a needle tip 30 of a projection element 22 within thesecond row 40 b is in rotational alignment between distal ends 36, 38 oftwo adjacent projection elements 22 within the first row 40 a. That is,the rotational offset between adjacent rows 40 a, 40 b can be such thatthe needle tip 30 of a projection element 22 within a row 40 isrotationally aligned with a needle tip 30 of a projection element 22 inevery other row. For example, the needle tips 30 in the first row 40 acan be rotationally aligned with the needle tips 30 in a third row 40 c,with the second row 40 b being both between and directly adjacent toeach of the first and third rows 40 a, 40 c.

The outer shell 16 of the tubular body 12 of the stent 10 can be formedfrom a thin sheet of material. According to some non-limiting examples,the outer shell 16 is formed of an elastomeric material (e.g., plastic,a polyester plastic, etc.). According to other non-limiting examples,the outer shell 16 can be formed of a metal, a polymer, or a composite.In some non-limiting examples, the outer shell 16 can be formed ofrigid, thin sheets of steel, nitinol, or plastic and the “elasticity” ofthe material can be provided by the pattern of cuts 20. In othernon-limiting examples, the outer shell 16 can be formed of soft flexiblematerials such as rubbers. In yet further non-limiting examples, theouter shell 16 can be formed of soluble polymers. The material of theouter shell 16 can have a shape memory, thereby allowing the projectionelements 22 of the outer shell 16 to repeatedly transition between thedeformed and undeformed states. According to some non-limiting examples,the outer shell 16 can define a wall thickness between about 0.01 mm andabout 2 mm. According to other non-limiting examples, the wall thicknesscan be between about 0.05 mm and about 1 mm. According to yet furthernon-limiting examples, the wall thickness can be between about 0.05 mmand about 0.5 mm. According to the illustrated non-limiting example,wall thickness is about 0.13 mm.

As previously described herein, the outer shell 16 of the tubular body12 can define a lumen (e.g., a hollow core) configured to receive anactuator 18. FIG. 5 illustrates one non-limiting example of the actuator18 configured to actuate the stent 10 between the extended and retractedpositions. In the illustrated non-limiting example, the actuator 18 is asoft fluid-powered actuator (e.g., a pneumatic actuator), although otherforms linear actuators are also possible. For example, the actuator canbe an electric, hydraulic, mechanical, or magnetic actuator. Accordingto other non-limiting examples, the actuator can be any form of actuatorconfigured to provide linear motion, such as a plunger or rod manuallycontrolled by a physician (e.g., a mechanical actuator), a piezoelectricactuator, a motor-powered actuator (e.g., a stepper motor). The actuator18 can include a cylindrical body 50 extending along the central axis 14from a first actuator end 52 to a second actuator end 54 opposite thefirst actuator end 52. The material of the cylindrical body 50 can havea shape memory, thereby allowing the cylindrical body to repeatedlytransition between the extended and retracted positions. According tosome non-limiting examples, the cylindrical body is formed of anelastomeric material (e.g., silicone-based rubber, latex, etc.).

The body 50 of the actuator 18 can define a hollow tube including aninterior cavity 56. According to some non-limiting examples, the body 50can define a wall thickness between about 0.01 mm and about 5 mm.According to other non-limiting examples, the wall thickness can bebetween about 0.05 mm and about 3 mm. According to yet furthernon-limiting examples, the wall thickness can be between about 0.05 mmand about 2 mm. According to the illustrated non-limiting example, wallthickness is about 1.5 mm.

The interior cavity 56 can extend through the body 50 between the firstactuator end 52 and the second actuator end 54. In the illustratednon-limiting example, the interior cavity 56 forms a first opening 58 atthe first actuator end 52 and a second opening 60 at the second actuatorend 54. The actuator can also include a plug 62 and a cap 64. The plug62 can be coupled at the second actuator end 54 of the actuator 18 toenclose the second opening 60. The plug 62 includes a plug boss 66 and aplug flange 68 at a distal end thereof extending radially outward fromthe plug boss 66. The plug boss can be configured to be received withinthe interior cavity 56 of the body 50. The plug flange 68 can beconfigured to abut the second actuator end 54 of the body 50, when theactuator 18 is in an assembled state (see, e.g., FIG. 2). According tosome non-limiting examples, the plug 62 can define a press-fit betweenthe plug boss 66 and the interior cavity 56 of the body 50 to form afluid impervious seal. According to the illustrated non-limitingexample, the plug 62 can be formed of an elastomeric material or a hardmaterial (e.g., a plastic).

The cap 64 can be coupled at the first actuator end 52 of the actuator18 to enclose the first opening 58. The body 50, plug 62, and cap 64together define and enclose the interior cavity 56. The cap 64 caninclude a cap boss 70 and a cap flange 72 at a distal end thereof andextending radially outward from the cap boss 70. The cap boss 70 can beconfigured to be received within the first opening 58. The cap flange 72can be configured to abut the first actuator end 52 of the body 50, whenthe actuator 18 is in the assembled state, to form a fluid imperviousseal with the body 50. According to the illustrated non-limitingexample, the cap 64 can be formed of an elastomeric material or a hardmaterial (e.g., a plastic). According to some non-limiting examples, thecap 64 can include a nylon plastic quick-turn plug.

The cap 64 can include an inlet port 74 and a fluid passage 76 in fluidcommunication with the inlet port 74. The fluid passage 76 is configuredto provide fluid communication between the inlet port 74 and theinterior cavity of the actuator 18. The inlet port 74 can extend axiallyoutward from the first end 21 of the outer shell 16 of the stent 10 (seeFIG. 2). The inlet port 74 can be configured to be coupled to apressurized fluid source 75 (e.g., compressed air), thereby allowingfluid from the pressurized fluid source to enter the interior cavity 56and extend or retract the actuator 18. In the illustrated non-limitingexample, the fluid passage 76 can be configured as a blunt needle (e.g.,a 20G blunt needle). In the illustrated non-limiting example, the inletport 74 can be configured as a barbed fitting.

Referring now to FIGS. 5 and 6, the body 50 can include a fiberreinforcement 78 configured to constrain the deformation of the actuator18 in the radial direction. Restricting the radial deformation canenable an increased performance in the axial direction forming anextensional actuator. The fiber reinforcement 78 can extends along atleast a portion of the axial length L_(A) of the actuator 18. Forexample, the fiber reinforcement 78 can extend along at least 50% of thelength L_(A) of the body 50. According to some non-limiting examples,the fiber reinforcement 78 can extend along between about 50% and about100% of the length L_(A) of the body 50. According to the illustratednon-limiting example, the fiber reinforcement 78 can extend alongbetween about 80% and about 95% of the length L_(A) of the body 50.According to some non-limiting examples, the fiber reinforcement 78 canbe formed of Kevlar fibers. According to other non-limiting examples,the fiber reinforcement 78 can be formed of metal fibers. According tosome non-limiting examples, the body 50 can be reinforced using rigid,circular rings along the length of the body 50 of the actuator 18. Forexample, a plurality of rigid (e.g., steel, nitinol, or plastic)circular rings can be arranged and axially separated along the length ofthe body 50 to prevent radial expansion of the body 50 and allow foraxial extension.

As best illustrated in FIG. 6, the fiber reinforcement 78 can includestrands of fibers arranged in a helical pattern. The fiber reinforcement78 can include a first helical strand 80 wrapped around the body 50 in afirst axial direction and a second helical strand 82 wrapped around thebody 50 in a second axial direction opposite the first direction,thereby forming the helical pattern. The helical pattern can be definedby a characteristic fiber angle β, as measured when the actuator 18 isin a retracted position. The fiber angle β can be described as the angleof the wrapping of either one of the first and second strands 80, 82relative to the plane 25 intersecting and orthogonal to the central axis14. According to some non-limiting examples, the helical pattern candefine a fiber angle β between about 1 degrees and about 60 degrees.According to other non-limiting examples, the helical pattern can definea fiber angle β between about 5 degrees and about 45 degrees. Accordingto yet further non-limiting examples, the helical pattern can define afiber angle β between about 5 degrees and about 30 degrees. According tothe illustrated non-limiting example, the helical pattern defines afiber angle β of about 10 degrees.

FIG. 7 illustrates another non limiting example of a stent 100. In theillustrated non-limiting example, unless otherwise described below orillustrated in the figure, like elements are labeled with like referencenumerals in the 100's (e.g., projection element 22 is labeled asprojection element 122). The stent 100 of FIG. 7 is substantiallysimilar to that of the stent 10 of FIG. 1, as such, only aspects thatdiffer from those previously described will be discussed. For example,in the illustrated non-limiting example, a first row 140 a ofcircumferentially spaced cuts 120 is rotationally offset from a second,adjacent row 140 b of circumferentially spaced cuts 120 by approximately180 degrees.

The projection elements 122 illustrated in FIG. 7 can include one ormore protrusions 184 located along the first and second edges 132, 134.The protrusions 184 can be configured to control a penetration depth ofthe projection elements 122 (e.g., needles) into the tissue of asubject. As best illustrated in FIG. 8, the penetration depth ofprojection elements (e.g., projection elements 22, 122, etc.) can becharacterized by the effective needle length H and the penetration depthd. The effective needle length H can be defined by a distance betweenthe needle tip 30 of the projection element 22 and either one of a base28 of the projection element (e.g., projection element 22 of FIG. 1) ora protrusion 184 of the projection element (e.g., projection element 122of FIG. 7). The penetration depth d can be defined as the radialdistance the needle tip of a projection element has penetrated into thetissue of a subject.

FIG. 9 illustrates one non-limiting example of a projection element 22,such as those illustrated in the stent 10 of FIGS. 1-4. In theillustrated non-limiting example, the first and second edges 32, 34 ofthe projection element 22 lacks any protrusions. FIGS. 10-12 illustratenon-limiting examples of protrusions 184 a, 184 b, 184 c, such as thoseillustrated in the stent 100 of FIG. 7, along the first and second edges132, 134 of the projection elements 122 defining various effectiveneedle lengths H (see FIG. 10). For example, the protrusions 184 (e.g.,184 a, 184 b, 184 c) can be arranged at a distance away from the needletip 130 that is between about 10% to about 95% of the total length ofthe projection element. According to some non-limiting examples, theprotrusions 184 can be arranged at a distance away from the needle tip130 that is between about 30% to about 95% of the total length of theprojection element.

As illustrated in FIG. 10, each of the first and second edges 132 a, 134a of the projection element 122 a include a round, dimple-shapedprotrusion 184 a. The protrusion 184 a can define a radius R. Accordingto some non-limiting examples, the radius R can be between about 0.1 mmand about 5 mm. According to other non-limiting examples, the radius Rcan be between about 0.5 mm and about 2.5 mm. According to theillustrated non-limiting examples illustrated in FIGS. 10-12, the radiusR is about 1.5 mm.

FIG. 13 illustrates another non limiting example of a stent 200. In theillustrated non-limiting example, unless otherwise described below orillustrated in the figure, like elements are labeled with like referencenumerals in the 200's (e.g., projection element 22 is labeled asprojection element 222). The stent 200 of FIG. 13 is substantiallysimilar to that of the stent 10 of FIG. 1, as such, only aspects thatdiffer from those previously described will be discussed. In theillustrated non-limiting example, the plurality of projection elements222 can include one or more etched striations 286 (e.g., lines) formedinto the outer surface of the outer shell 216.

As best illustrated in FIG. 14, the projection element 222 can include aplurality of striations 286. The striations 286 can be configured toprovide a more robust surface for the loading of therapeutic agents orcoatings onto the projection elements. For example, the striations 286can improve adhesion between the surface of the outer shell 216 and atherapeutic coating or surface coating layer. The plurality ofstriations 286 can be shaped similar to the triangular projectionelement 222, such that the lines formed by the striations 286 aresubstantially parallel (e.g., evenly offset from) the first and secondedges 232, 234 of the projection element 222. According to somenon-limiting examples, the projection element 222 can include betweenabout 1 and about 20 striations 286. According to some non-limitingexamples, the projection element 222 can include between about 1 andabout 10 striations 286. In the illustrated non-limiting example, theprojection element 222 includes six striations 286. The striations 286can be evenly separated (e.g., offset from) an adjacent striation. Forexample, the pattern of striations 286 can define a spacing betweenadjacent striations 286 that is between about 0.05 mm and about 2 mm.According to some non-limiting examples, the pattern of striations 286can define a spacing between adjacent striations 286 that is betweenabout 0.1 mm and about 1 mm. According to the illustrated non-limitingexample, the pattern of striations 286 defines a spacing betweenadjacent striations 286 that is about 0.5 mm.

Referring now to FIG. 15, stents (e.g., stent 10, 100, 200, etc.) can beconfigured as drug eluting stents. For example, at least a portion ofthe stent can be coated in a therapeutic agent. According to onenon-limiting example, the projection elements 222 of the stent 200 canbe coated with a therapeutic agent in the form of drug particles 288(e.g., drug-loaded polymeric particles) to enable the local delivery oftherapeutics to submucosal tissues through circumferential injectionswithin the tubular structure of the GI tract or trachea of a subject.According to one non-limiting example, the projection elements 222(e.g., needles) of the stent 200 can be coated by pipetting atherapeutic agent via a pipet 290. The therapeutic agent can beentrapped or concentrated on the projection elements 222 via thestriations 286 thereon. According to some non-limiting examples, thestent 200 can include polymeric sacrificial layers surrounding the stent200 that are configured to protect the drug-coated particles, which canalso increase drug loading capacity.

According to one non-limiting example, the therapeutic agent can includean anti-inflammatory drug (e.g., budesonide, prednisone, colchicine,resveratol, etc.), and anti-proliferative drugs (e.g., paclitaxel,everolimus, sirolimus, among other -limus agents, etc.), for delivery towalls of the GI tract or trachea. Budesonide, for example, is ananti-inflammatory drug commonly used to treat inflammatory bowel diseaseand eosinophilic GI disorders. In the illustrated embodiment, budesonidecan be encapsulated into poly lactic-co-glycolic acid (“PLGA”)microparticles using a continuous microfluidic droplet generation method(generally illustrated in FIG. 15). According to some non-limitingexamples, the drug particles 228 can be formulated with variousconcentrations of the therapeutic agent. For example, budesonide loadedPLGA particles can be used with 75, 100, or 125 mg/ml concentration ofbudesonide (denoted by BUD 75, BUD 100, and BUD 125, respectively).Additionally, a concentration (e.g., 100 mg/ml) of fluorescentbudesonide-PLGA particles (denoted BUD 100F) can be added via afluorescent agent configured to allow for confirmation of thetherapeutic agent delivery using various forms of imagery.

In the above description, reference is made to various dimensions,parameters, and characteristics of the stent 10 and its components. Itis to be understood that these components can be sized based on theintended application. For example, within the GI tract, stents 10 can beconfigured for placement within the stomach, esophagus, colon, smallintestine, or large intestine. Dimensions and parameters of the stents10 can be chosen based on the application or dimensions of the tubularstructures of the GI tract or trachea for a given subject. For example,depending on the target position of deployment of the stent, a desireddiameter and length of the stent may be determined (i.e., based on adiameter and length of the target position). Based on a determineddiameter and length of the stent, the pattern of cuts 20 (e.g., needle,length, cut angle, hinge length, etc.) can be determined such that theresulting kirigami stent 10 expands to reach a desired penetrationdepth. For example, hinge length can be determined or calculated basedon needle length, cut angle, thickness, and/or material of the outershell 16 to provide the pop-up deployment motion of the projectionelements 22.

Methods of Inserting/Removing a Kirigami-Inspired Stent

Referring now to FIGS. 1, 2, and 16, the kirigami-inspired stents 10 arecapable of reversible shape transformation from a retracted position(FIG. 2), in which the projection elements 22 are in a flat, undeformedstate resulting in a smooth outer surface of the outer shell 16, to anextended position (FIG. 1), in which the projection elements 22 aretransitioned into a deformed state and configured to provide popped-upneedles configured for injections into a tissue of a subject. With thetubular body 12 of the stent 10 in the retracted position, the stent 10can be delivered and removed from tubular structures within the subject(e.g., GI tract or trachea). With the tubular body 12 of the stent 10 inthe extended position, the projection elements 22 (e.g., needles) of thestent 10 can deliver circumferential injections to pierce the tissue ofthe subject, and according to some non-limiting examples, deliver atherapeutic agent into the injection sites. Thus, the stent systemsdescribed herein can provide facile, in vivo delivery, robustdeployment, and safe removal of a stent configured for injections, andaccording to some non-limiting examples, providing a drug releasingsystem. It is to be understood that the following method 300 can beapplied to each of the stents described herein (e.g., stent 10, 100,200). In the following description reference will be made to the stent10 of FIGS. 1-4.

The method can begin at 302 by inserting the stent 10 into a tubulartissue structure of a subject in a first, insertion direction (e.g.,relative to the central axis 14). For example, the stent 10 can beinserted into the GI tract (FIG. 17) or the trachea (FIG. 18) byapplying a pushing force to the first end of the tubular body 12 of thestent 10. During insertion, the stent 10 is in the retracted position(FIG. 2) with the actuator 18 unpressurized. According to somenon-limiting examples, a tube dimensioned to receive the stent 10therein can be inserted into the tubular structure of the subject priorto insertion of the stent 10. The tube can be configured to guidedelivery of the stent 10 to a tissue site of interest.

Once the stent 10 is positioned at the tissue site of interest, theactuator 18 can be actuated 304 from the retracted position towards theextended position, thereby deploying the projection elements 22 radiallyoutward into the deformed state. For example, the actuator 18 can bepressurized by the pressurized fluid source 75 coupled to the inlet port74 and the actuator 18 can begin to elongate to engage the enclosedfirst and second ends 21, 23 of the outer shell 16 of the tubular body12, thereby elongating the outer shell 16 and deforming the projectionelements 22 to deploy radially outwards.

With the stent 10 in the extended position, the projection elements 22can engage 306 the tissue of the subject to form a pattern ofcircumferential injection sites into the tissue. According to somenon-limiting examples, the stent 10 can be moved in a second, removaldirection by applying a pulling force to the first end of the tubularbody 12 of the stent 10. By moving the stent 10 in the second directionwith the projection elements 22 deployed, the projection elements can befurther driven into the tissue of the subject to increase the insertiondepth of the projection elements 22. For example, the projectionelements 22, when deployed, generally extend from the second end 23towards the first end 21 of the tubular body 12, owing to the needleangle θ (see, e.g., FIG. 3). Thus, movement of the stent 10 in thesecond direction (towards the first end 21) can drive the projectionelements 22 into the tissue of the subject.

As previously described, the projection elements 22 can be loaded with atherapeutic agent (see, e.g., FIG. 9), and insertion of the projectionelements 22 can be configured to deposit the therapeutic agent (e.g., inthe form of drug particles 288) at the circumferential injection sites.According to some non-limiting examples, the stent can be left in placefor a period of minutes, hours, or days (e.g., up to a week or more) toprovide prolonged delivery of the therapeutic agent via the drug-loadedprojection elements 22.

For removal of the stent 10, the stent 10 can be moved in the firstdirection (towards the second end 23) to remove the projection elements22 from the tissue of the subject. With the projection elements 22removed, the stent 10 can be actuated from the extended position towardsthe retracted position to stow the projection elements into theundeformed state. Once the stent 10 is in the retracted position, thestent 10 can be removed from the subject by moving the stent 10 in thesecond, removal direction, for example, by again applying a pullingforce to the first end of the tubular body 12 of the stent 10.

Methods of Making a Kirigami-Inspired Stent

Referring now to FIGS. 19-21, a non-limiting example of a method 400 ofmaking the actuator 18 for the stent 10 is illustrated. It is to beunderstood that the following method 400 can be applied to each of thestents described herein (e.g., stent 10, 100, 200). In the followingdescription reference will be made to the stent 10 of FIGS. 1-4. Asillustrated in FIG. 19, the body 50 of the actuator 18 can be formed viaa casting or injection molding process 402. The casting or injectionmolding process can include providing a multi-piece mold 410 (FIG. 19),including a first part 412 forming the interior cavity 56, and secondand third parts 414, 416 forming the body 50. In the illustratednon-limiting example, the second and third parts 414, 416 of the mold410 can include a pattern of helical protrusions 418 configured to formhelical recesses 420 along the body 50 to receive the fiberreinforcement 78 (FIG. 20).

According to some non-limiting examples, the mold 410 can be sprayedwith a releasing agent for easy demolding. Then, the elastomericactuator body 50 and plug 62 can be cast separately using an elastomericmaterial (e.g., a silicone-base rubber, vinylpolysiloxane, a-silicone).According to some non-limiting examples, the elastomeric material can bea duplicating elastomer (e.g., Elite Double 8). The casted mixture canbe mixed for a predetermined period of time (e.g., two minutes), placedin a vacuum for degassing, and then allowed to set at a predeterminedtemperature (e.g., room temperature) for a predetermined period of time(e.g., thirty minutes) to cure.

With the body 50 formed, strands of fiber reinforcement material can bewrapped 404, 406 within the helical recesses 420 along the body 50 (FIG.21) to form the helical-patterned fiber reinforcement 78. According tosome non-limiting examples, a uniform thin layer of a silicone adhesivecan be applied to the outer surface of the fiber-reinforced actuatorbody 50 to enhance the bonding between the fiber and elastomer. Theextensional actuator body 50 can then be left to cure at a predeterminedtemperature for a predetermined period of time (e.g., room temperaturefor 30 min), allowing the silicone adhesive to dry. Then, the plug 62and the cap 64 can be coupled with the body 50 (e.g., via an adhesive)to seal the interior cavity 56 (see FIG. 5).

Referring now to FIGS. 22-24, a non-limiting example of a method 500 ofmaking the outer shell 216 for the stent 200 is illustrated. It is to beunderstood that the following method 500 can be applied to each of thestents described herein (e.g., stent 10, 100, 200). In the followingdescription reference will be made to the stent 200 of FIGS. 13-14. Asillustrated in FIG. 22, the stent 200 can be cut 502 from a flat sheetof material, and then later formed into a cylindrical shell 508. In theillustrated non-limiting example, the cuts 220 were formed via a lasercutter 510 (e.g., a CO₂ laser). In the specific illustrated non-limitingexample, the stent 200 is composed of a periodic array of 2×13projection elements 222 (e.g., 26 projection elements). Although, otherconfigurations of arrays and total number of projection elements arealso envisioned. As illustrated in FIG. 22, the laser cutter 510 canalso form the etched striations 286 on the outer surface of the outershell 216. For example, the laser cutter 510 can form the cuts 220 at afirst power and the striations 286 can be formed at a second power thatis lower than the first power.

According to some non-limiting examples, the outer shell 216 can includesmall apertures 292 perforated along lateral edges of the outer shell216, which can be used to facilitate alignment when formed into acylindrical shape. According to the illustrated non-limiting example,circular cutouts 294 can be coupled to the first and second ends 221,223 of the outer shell 216. The circular cutouts 294 can be configuredas end caps for the outer shell 216 when formed into a cylindricalshape. In the illustrated non-limiting example, the circular cutouts 294can include one or more tabs 296 extending outward from the circularcutouts 294. The tabs 296 can be configured to be coupled to the firstand second ends 221, 223 of the outer shell 216 (e.g., via an adhesive)to secure the circular cutouts 294 to the outer shell 216. The circularcutout 294 arranged at the first end 221 of the outer shell 216 caninclude a central aperture 298. The central aperture 298 can beconfigured to receive the inlet port 274 (see FIG. 13) such that theinlet port 274 can extend axially away from the outer shell 216 throughthe first end 221 thereof.

As illustrated in FIG. 23, some surfaces (e.g., such as plastic surfacesor surfaces comprised of elastomeric materials) can be hydrophobic,which can lead to incompatibility with surface coatings, such astherapeutic agent coatings. To increase the adhesion bond to surfacecoatings, an air plasma treatment 504, 506 can be utilized to microclean and alter the surface properties of the kirigami surfaces foradhesion improvement. According to one non-limiting example, thesurfaces of the outer shell 216 can be treated in air plasma 506 withhigh radio frequency for a predetermined period of time (e.g., at 500mTorr for 1 hour) using a plasma cleaner device (e.g., a high powerexpanded cleaner). The plasma treatment results in the creation ofhydrophilic surfaces of the outer shell 216 and improvement in theadhesive bond created between the outer shell 216 and surface coatings,such as therapeutic agent coatings like a drug-coated film, that canfacilitate the drug solution coating and enhance the drug filmstability.

According to some non-limiting example, a surface coating can include aradiopaque coating. For example, at least a portion of the outer shell216 can be coated in a radiopaque coating. The radiopaque coating canmake the outer shell 216 of the stent 200 radiopaque. According to somenon-limiting examples, the entire outer shell 216 can be coated with theradiopaque coating. According to other non-limiting examples, at leastthe projection elements 222 can be coated with the radiopaque coating.According to some non-limiting examples, the outer shell 216 can becoated with a thin layer of tungsten filled conductive ink (e.g., RO-948Radio Opaque Ink, MICROCHEM).

Finally, as illustrated in FIG. 24, the outer shell 216 can be formedinto a cylindrical-shaped shell and the lateral edges can be coupledtogether (e.g., via an adhesive) with the outer surface with thestriations 286 facing outward. In this configuration, the outer shell216 can then receive an actuator (e.g., actuator 18, FIG. 5). Once theactuator 18 is within the outer shell 216, the circular cutouts 294 canbe coupled to enclose the first and second ends 221, 223 (e.g., via anadhesive) (see, e.g., FIG. 13).

EXAMPLES

The following description includes particular non-limiting examples ofstents that utilize the systems and methods previously described herein.The following examples are not intended to limit the disclosure. In thefollowing description, a systematic study is described, in which theproperties of the stents described herein are characterized usingvarious parameters and tests.

As described herein, the stents (e.g., stents 10, 100, 200) can includea cylindrical kirigami skin that includes a periodic array of snakedenticle-like cuts, which can be embedded in thin plastic sheets.According to some non-limiting examples, color-coded polyester plasticshim stocks can be used to fabricate the kirigami surfaces with snakeskin-like needles. To measure the material properties of the shimstocks, uniaxial tensile tests were carried out on the 80 mm×43 mmplastic specimens with a range of thicknesses, t=0.05, 0.08, 0.10, 0.13,0.19 mm, according to ASTM D882-18 (Standard Test for Tensile Propertiesof Thin Plastic Sheeting). A uniaxial testing machine (e.g., an Instron5942 series Universal Testing System) with a 500 N load cell was used totest specimens. All the tests were conducted under uniaxial tensileloading by applying a constant displacement rate of 0.5 mm/squasi-statically until the 500 N load cell threshold. The response ischaracterized by linear elastic region followed by a plateau. Nominalstress-strain curves can be seen in FIG. 25. E=3.655 GPa and v=0.4 werethe measured Young's modulus and Poisson's ratio of the plastic shimstocks, respectively.

The stents can also include a pneumatic fiber-reinforced soft actuatormade of a 1.5 mm thick silicone-based rubber. The silicone-based rubbercan be Vinylpolysiloxane (a-silicone) duplicating elastomer (e.g.,“Elite Double 8”) was used to cast the soft actuator. To measure thematerial properties, three dog-bone specimens (FIG. 26, gauge length,h₀, of 33 mm, width, a₀, of 6 mm, and thickness, t₀, of 3 mm) were castand tested under uniaxial tensile loading according to ASIM D412 TestMethod (Standard Test Methods for Vulcanized Rubber and ThermoplasticElastomers, Tension). A uniaxial testing machine (e.g., an Instron 5942series Universal Testing System) with a 500 N load cell was used to testspecimens. As illustrated in FIG. 27, one end of each specimen was fixedusing screw side action grips, and a constant displacement rate of 500mm/min applied to the other end quasi-statically. The stress-strainresponse of the material (i.e., nominal stress vs. nominal strain) wasmonitored up to the elastomer rupture at ε˜6 (FIG. 28). The nominalstress, σ²², is defined as the force applied on the deformed sample,divided by the cross-sectional area of the undeformed sample. Asillustrated in FIG. 28, the rubber has Poisson's ratio of v₀=0.499,density of ρ=1.0E3 kg/m3, and initial elastic modulus of E₀=79.267 KPa.

The pneumatic fiber-reinforced soft actuator can provide a linear motionto induce tensile strain in the kirigami skin and trigger the needles topop out. The radial expansion (ε^(r)) and axial extension (ε^(a)) of thestent and popping angle of the needles (θ) can be tuned by controllingthe actuator pressure (P/P₀), where P₀=1 atm.

For example, FIG. 29 illustrates the radial strain and needle angle as afunction of actuator pressure. As illustrated, the needle angle theneedle angle θ can be substantially proportional to the actuatorpressure. In the illustrated non-limiting example, the needle angle θcan be linearly proportional to the actuator pressure. For example, asillustrated, ε^(r) and θ are monotonically increased by 0.12 and 20°through applying pressure up to 5.8 atm for the with initial length L₀=8cm and outer diameter D₀=12.5 mm.

Numerical models of the kirigami stents can be constructed withdifferent combinations of t and l, and non-linear finite elements (FE)analyses can be employed to capture the deformation of the stentssubjected to the applied actuator pressure using a FE package such asABAQUS/Explicit. All the simulations were carried out using thecommercial Finite Element (FE) package ABAQUS 2017. The Abaqus/Explicitsolver was employed for the simulations. FE models were constructed ofthe elastomer actuator, Kevlar fiber, nylon plastic plug, and kirigamiplastic shell to investigate the deformation response of the kirigamistent.

A linear elastic material model was used for Kevlar fiber, polyesterplastic, and nylon plastic. Kevlar fiber has a density of 1.13E3 kg/m3,Young's modulus of 31067 MPa, and Poisson's ratio of 0.36 with acircular beam section of 0.0889 mm radius. Polyester plastic sheet has adensity of 1.13E3 kg/m3, Young's modulus of 3655 MPa, Poisson's ratio of0.4 with shell section of 0.127 mm thickness. The nylon Plastic has adensity of 1.15E3 kg/m3, Young's modulus of 4000 MPa, and Poisson'sratio of 0.36. The constitutive behavior of the elastomer was capturedusing a nearly-incompressible Neo-Hookean hyperelastic model (Poisson'sratio of v_0=0.499 and density of 1.0E3 kg/m3) with directly importeduniaxial test data described in “Material characterization” forsilicone-based rubber.

Different element types were used to construct the three-dimensional(3D) FE models of the kirigami stent. Linear beam element (Abaquselement type B31, seed size=1) for the Kevlar fibers, 3D shell elementwith reduced integration (Abaqus element type S4R, seed size=1) for theplastic kirigami, and 3D brick element (Abaqus element type C3D8, seedsize=1.5) for the elastomer actuator and the plastic plug. The DynamicExplicit solver with a time period of 1000 and a mass scaling factor of1000 (to facilitate convergence) was used. TIE constraint (surface tosurface) was applied between the fibers and the elastomeric body.General Contact type interaction with penalty friction coefficient 0.2for tangential behavior and “hard” contact for normal behavior wereapplied. Finally, the pressure load applied to the inner surface of thelinear actuator using SMOOTH step amplitude curve, and the deformationof the kirigami stent model was monitored as a function of the appliedpressure.

Using the numerical methods, as will be described below, an optimalstent design was identified that exhibits larger radial expansion(ε^(r)) and higher out-of-plane stiffness of the needles (K³³) forbetter engagement with the surrounding tissue and injection whileactuated.

A systematic study was carried out to predict the effect of t (thethickness of the outer shell of the stent) and l (the needle length) onthe evolution of ε^(a), ε^(r), and θ as a function of the appliedactuator pressure (P/P₀) for an esophageal-sized stent with L₀=8 cm andD₀=12.5 mm. The deformation response of the kirigami stents can becontrolled by varying the thickness of the kirigami shell (t) and theneedle length (l) as a function of applied pressure. For example, FIGS.30-33 illustrate the effect of l and t on the maximum actuator pressure(P_(max)/P₀, P₀=1 atm), maximum axial (ε_(max) ^(a)), radial (ε_(max)^(r)) strains, and maximum popping angle (θ_(max)) of a kirigamiinspired stent.

In the color maps shown in FIGS. 30-33, where the actuator pressureP_(max)/P₀ (FIG. 30) that achieves a corresponding ε_(max) ^(a) (FIG.31), ε_(max) ^(r) (FIG. 32), and θ_(max) (FIG. 33) of the stent isreported. Geometrical parameters were explored, ranging from t=0.05,0.08, 0.10, 0.13, 0.19 mm and l=10.0, 6.7, 4.8, and 3.0 mm. The figuresindicate that by increasing l, ε_(max) ^(r) considerably rises, andε_(max) ^(a), θ_(max), and P_(max)/P₀ slightly increase for a given tTherefore, l=10.0 mm was selected as a good candidate for needle lengthto achieve maximum radial expansion. Furthermore, by increasing t,P_(max)/P₀ increases at constant l, however, ε_(max) ^(a), ε_(max) ^(r),and θ_(max) are almost remained unaltered.

To identify a preferred t for a given stent geometry, kirigami surfaceswere fabricated with various thicknesses, and experimentallyinvestigated the effect of t on the stiffness of the kirigami needles inthe normal direction, denoted by K³³. To measure the stiffness, a normalstiffness test was carried out (e.g., using an Instron 5942 seriesUniversal Testing System). First, the surfaces were uniaxially stretchedto different levels of strains, ε{circumflex over ( )}22=0, 0.5, 0.10,0.15, and 0.20, which result in buckling out the needles. At each levelof applied strain, the surfaces were immobilized to an acrylic plate andthen compressed in the vertical direction, as illustrated in FIG. 34.Surfaces with barb-shaped needles made of plastic were tested. For eachlevel of strain, the surfaces were compressed at a constant rate of 1mm/s until flattened using a 500 N load cell. The compression force as afunction of vertical displacement was recorded. The normal initialstiffness (N/mm) was then estimated by calculating the initial slope ofthe force-displacement curves. This was repeated three times per levelsof applied tensile strain.

FIG. 35 demonstrates that increasing t, significantly increases theout-of-plane stiffness of the needles. Therefore, choosing a thickerkirigami can result in stiffer needles that can provide easierpenetrations. Since the kirigami with the maximum thickness (t=0.19 mmin grey) shows localized plastic zones at the hinges that slightlyaffects the reversible deformation of the needles (i.e., return to theinitial flat configuration after releasing the load) needed for saferemoval.

As previously described, the kirigami shell (or stent) is capable ofreversible shape transformation from flat configuration (for devicedelivery and removal) to 3D surfaces with popped-up needles (forinjections) that enables facile delivery, robust deployment, and saferemoval of the drug releasing system. FIG. 36 illustrates kirigamisurfaces under uniaxial tensile loads. FIG. 37 illustrates experimentalimages showing undeformed and buckled configurations of the kirigamiprototype under different levels of applied strain ε{circumflex over( )}22=0, 0.1, 0.2, 0.3, and 0.4. FIG. 38 Nominal stress-strain responseof the kirigami surfaces with various thicknesses t=0.05, 0.08, 0.10,0.13, 0.19 mm subjected to uniaxial tensile strain ε{circumflex over( )}22 for n=3 measurements. Given the systematic testing results, thekirigami with t=0.13 mm was selected as a preferred thickness for makingthe kirigami shell at the given stent geometry. Having identified l=10.0mm and t=0.13 mm as ideal design parameters that provide simultaneoushighest ε^(r) and K³³, along with having reliable reversible shapetransformation, the stent prototypes were fabricated, and theirperformance was experimentally evaluated.

Referring now to FIG. 39, Numerical and experimental images of theesophageal stent at different levels of actuator pressure, P=1.0, 1.5,2.7, 3.4, 4.4, and 5.2 atm, where P=1.0 and 5.2 atm correspond toundeformed and fully deployed configurations, respectively. L₀=8 cm andD₀=12.5 mm are the initial length and outer diameter, and L, D, and θare the length, outer diameter, and popping angle of the stent for agiven P, respectively. The kirigami stent in the illustrated images isformed from an 80×43 mm surface consisting of a periodic array of2×13=26 stretchable needles. FIGS. 40-42 illustrate the evolution ofaxial strain (ε^(a)) (FIG. 40), radial strain (ε^(r)) (FIG. 41), andpopping angle (θ) (FIG. 42) plotted as a function of P/P₀. Numericalcalculations (red dashed line) are compared to experimental (bluemarkers) results. The markers represent the mean±SD for n=22 needlemeasurements for each group.

The experimental images were compared to the numerical snapshotsobtained from non-linear FE simulations, showing that the kirigami shellis initially flat and then transform into 3D configurations with buckledout or protruding needles upon pressurizing the actuator. By releasingthe pressure, the needles are popped in or retract and recovered theiroriginal undeformed shape. The deformation of the prototype wasquantified and the experimental data (blue markers) was compared to theFE results (red dashed lines), showing a close agreement. The evolutionof axial extension (ε^(a)=L/L₀), radial expansion (ε^(r)=D/D₀), andpopping angle (θ) as a function of the actuator pressure (P/P₀)illustrated in FIGS. 40-42 demonstrate a gradual linear increase inε^(a), ε^(r), and θ due to out-of-plane buckling of needles, and then aplateau at higher pressure up to P/P₀=6.5 results in ε_(max) ^(a)=0.36,ε_(max) ^(r)=0.57, and θ_(max)=28°. This considerable expansion of thestent especially in the radial direction allows a close engagement ofthe popped-up needles against the tissue of a subject.

Finally, to ensure the ability to fabricate the stents in multiple sizesand consistency with this numerical prediction, further esophagealstents were fabricated with multiple combinations of t and l, and theirdeformation was characterized using both FE simulations and experiments,showing an excellent qualitative agreement. FIG. 43 (top) illustrateskirigami surface prototypes comprised of a period array of needles withvarious needle's lengths l=10.0 (left), 6.7 (middle), and 4.8 (right) mmmade of t=0.13 mm kirigami surface. FIG. 43 (bottom) illustrates stentprototypes corresponding to the top kirigami surfaces at undeformed andactuated (at P/P_0=3.5 atm) configurations.

Evaluation of Controlled Penetration of Stent Needles to the GI Mucosa.

Micro-computed tomography (micro-CT) imaging and histology from ex vivoand in vivo experiments have been employed to demonstrate that the stentneedles can be inserted by more than 1 mm into the submucosa of swineesophageal tissue without causing perforation. The penetration depth ofthe needles (d) can be controlled by incorporating the arc-shapedfeatures (i.e., dimples with R=1.5 mm) on the two sides of theprojection elements (i.e., needles) as illustrated in FIG. 44. Thesesmall features can stop further penetration when contacting the tissuesurface. The dimples were positioned at a characteristic distance H fromthe tip of the needles. The experiments considered H=1.5, 2.5, 3.5 mm,and no dimple (control). To quantify d, stents were deployed in vitroand brushed with a thin layer of tungsten filled radio-opaque ink in theesophagi harvested from Yorkshire pigs using a custom 3D printedfixture.

To make the external surface of kirigami stent (especially the needles)radiopaque, the flat kirigami surfaces were coated with a thin layer oftungsten filled conductive ink (RO-948 Radio Opaque Ink, MICROCHEM)using a roller. The coated kirigami surface was left overnight to dry.The radiopaque stent prototypes with different needle's lengths (H) weredeployed in the esophagus harvested from a Yorkshire pig. The esophaguswas rinsed for approximately 10 sec under running tap water to wash awaycontaminants such as gastric fluid. To deploy the stent, a custom 3Dprinted fixture was used. The fixture consisted of a 20 mm diameter tube3D printed out of VeroClear plastic. The 20 mm tube was placed insidethe ex vivo esophagus to hold it open for deployment, and the stent witha given needle's length inserted into the esophagus via the tube. Onceit reached the proximal esophagus, the pneumatic linear actuator insidethe stent was inflated by pumping air using a plastic syringe connectedto the stent (e.g., via the inlet port) via a Tygon PVC clear tubingresults in popping up the needles. Syringe stopcock was used to maintainthe pressure inside the stent's pneumatic actuator and keep all theneedles popped up at the maximum angle (˜22°) against the surroundingesophageal tissue. The kirigami needles were inserted into the tissue bygently pulling the Tygon tubing backward via application of ˜8N force.

The deployed stent in the esophagus was then transferred into themicro-CT scanner and scanned following the protocol for soft tissue.Using the image viewer software, the penetration of the needles into thetissue was monitored by taking tomographic images at multiple views. Thepenetration depths were measured using both the cross-section and topviews, where we were able to see the needle tips penetrated to theesophageal submucosa. The precise depths were obtained through measuringthe distance between the inner surface of the tissue and the tip of theneedles, d, as shown in FIG. 45.

FIG. 45 shows the representative 3D micro-CT image of the deployed stentand 2D cross-sectional slices used to obtain d. The data were reportedin the plot (e.g., FIG. 44), showing d=0.549±0.092, 0.914±0.156,0.926±0.176, and 0.932±0.148 mm for the stents made with H=1.5, 2.5, 3.5mm, and no dimple, respectively (mean±SD, n≥10).

Note that all the needles were penetrated into tissues with an averagetilting angle θ˜22°, which is the maximum popping angle (considering thesurrounding tissue wall) achieved by pressurizing the soft actuator upto P_(max)/P₀=6.5 and gently pulling it backward via application of ˜8 Nforce. Therefore, the maximum penetration depths (d_(max)) werepredicted as d_(max)=H sin θ=0.57, 0.96, and 1.34 mm for the needles 1to 3 (dashed lines in FIG. 44 plot). For the needles with H=1.5 mm and2.5 mm, the experimental results matched with the predicted d_(max)verifying that the dimples were able to stop the insertion of theneedles. However, the needle with H=3.5 mm did not reach demonstratingthat for the given 8 N pulling force, the penetration depth of thatneedle is equivalent to the control needle that has no dimple. To ensurethe safety margin on the insertion depth, the kirigami stent made of thecontrol needle was deployed in vivo in pigs.

The kirigami stent prototypes were deployed for in vivo evaluations in alarge animal model (50 to 80 kg female Yorkshire pigs ranging between4-6 months of age). The pig was chosen as a model because its gastricanatomy is similar to that of humans and has been widely used in theevaluation of biomedical GI devices. An overtube (with D_in=⅝″ andD_out=¾″—US Endoscopy), with endoscopic guidance, was placed into theproximal esophagus to assist the placement of the stent. The stent with8 cm length and 12.5 mm diameter was inserted into the esophagus via thetube pushed by the end of a scope. Once it reached the proximalesophagus, the overtube was removed, results in exposure of the stent tothe esophageal mucosa. Similar to the ex vivo deployment, the pneumaticlinear actuator inside the stent was actuated by pumping air using aplastic syringe connected to the stent via a Tygon PVC clear tubingcaused buckling up the needles. Syringe stopcock was used to maintainthe pressure inside the pneumatic actuator and keep all the needlespopped up against the mucosa. The kirigami needles were then insertedinto the submucosa by gently pulling the Tygon tubing backward viaapplication of ˜8 N force. After deployment, the stent was left in placefor 2 minutes before retrieval. The stent was then retracted byreleasing the actuator pressure that makes the needles to buckle in andrecover its original shape for easy removal.

As illustrated in FIG. 48, a histological image analysis was performedof the esophageal tissues at the penetration sites, showing d=1.09±0.16mm without perforation when 8 N force was applied. Biopsies were takenat the penetration sites of the harvested esophagi, where needles coatedwith tissue marking dye penetrated. The biopsies were fixed in formalinfixative for 24 hours before transfer to 70% ethanol. Tissue sampleswere then embedded in paraffin, cut into 5 μm-thick tissue sections, andimaged (e.g., by using an Aperio AT2 Slide Scanner).

In Vivo Delivery of Fluorescent Polystyrene Microparticle

To enable loading and delivery of polymeric particles with theinjectable stent system, the external surface of the stent (i.e.,kirigami shell) was coated with a solution of fluorescent magneticpolystyrene microparticles. Fluorescent magnetic polystyrenemicroparticles (Fluorescent Nile Red Magnetic Particles, 1.0% w/v,4.0-4.9 μm nominal size) and 25% w/v of Dextran sulfate sodium salt indouble-distilled H2O Water were mixed with a ratio of 5:2. 10% w/w ofglycerol as a plasticizer was added to the mixture. The final mixturewas vortexed for 10 minutes before coating.

A custom-built benchtop spray coating set-up with programmable stentmovement and rotation was used to achieve a uniform thin film coating ofthe solution onto the kirigami stent shell, shown in FIG. 49. In theillustrated example, an airbrush controlled by a micro-fluidic pump andflow sensor was used to spray-coat the kirigami stent prototypes withfluorescent particle solution. The set-up 550 includes: nitrogen gastank 552, standard infusion syringe pump 554, 20 rpm rotary fixture 556,3D printed rotary shaft 558, airbrush 560, kirigami stent prototype 562(e.g., stent 10, 100, 200), pressurized vessel containing the coatingsolution 564, micro-fluidic pump with a flow sensor 566, and PCcontrolling unit 568. The snapshots of the coating process at differenttime points (0, 5, 15, and 30 min) are illustrated in the bottom row ofFIG. 47. One end of the shaft 558 was connected to a 20 rpm rotaryfixture 556, while the other end held the stent prototype 562. Therotary fixture 556 was secured to a syringe pump 554 head, whichprovided a linear motion with 15 ml/min infuse or withdraw rate for a 50ml target volume per coating step. This resulted in forward and backwardmotion (corresponding to infuse and withdraw steps) of the stent 562with 24 mm/min speed for 8 cm displacement under a fixed airbrush 560,while the stent 562 rotates during the whole coating process. Such arotation and linear motion ensure that the whole stent is covered with auniform coating layer.

The airbrush 560—used to spray the coating solution through itsnozzle—was connected with a silicone tubing to a 30 ml pressurizedcoating solution vessel 564 and placed on a magnetic stirrer forcontinuous mixing, feeding and spraying the solution. The vessel 564 wasequipped with a pressure pump 566 controlled by software (e.g., on thePC controlling unit 568). Two nitrogen gas tanks 552 were used to supplypressure for the pressure pump 566 (400 KPa) and airbrush 560 (50 KPa)during the coating process. The feeding pressure was optimized (5-60KPa) and set to 40 KPa (equal to 40 μl/min) to reach a constant solutionflow and uniform spraying pattern. The whole coating process consistedof eight coating steps (four infuse and four withdraw).

The fluorescent magnetic microparticles were delivered in vivo in threeporcine esophagi using the coated prototypes (FIGS. 48 and 49), whichdemonstrate a periodic array of higher fluorescent concentration spotsat the kirigami needle penetration sites, further supporting thecapability of this drug delivery system to administer polymericparticles to the GI tract. As illustrated in FIG. 48, the fluorescentred magnetic particles deposition in the harvested esophagus wasassessed by taking a 2D epi-fluorescence image using an IVIS (in vivoimaging system) Spectrum in vivo imaging system at fluorescentexcitation and emission filter set of 570 nm and 620 nm, respectively.

Similar kirigami-based stents with proper size and needle stiffness wereprototyped to demonstrate the ability of safe delivery andcircumferential injection of fluorescent microparticles in other tubularparts of the body including femoral arteries and trachea. For example,as illustrated in FIG. 50, histological images are illustrated of atrachea that was penetrated with kirigami-based stent needles having atissue marking die thereon.

In vivo sustained drug release through deposition of polymeric particlesloaded with therapeutics

To evaluate the performance of the kirigami stents for extended drugrelease, in vivo studies were conducted in swine, and using budesonideas a model drug, demonstrating that the injectable stent delivers drugdepots for up to a week through multipoint submucosal deposition ofdrug-loaded polymeric particles. Budesonide, an anti-inflammatory drugcommonly used to treat inflammatory bowel disease and eosinophilic GIdisorders, was encapsulated into poly lactic-co-glycolic acid (PLGA)microparticles using continuous microfluidic droplet generation method.Three formulations of budesonide loaded PLGA particles with 75, 100, and125 mg/ml concentration of budesonide, were formulated and are denotedby BUD 75, BUD 100, and BUD 125, respectively. Additionally, 100 mg/mlconcentration of fluorescent budesonide-PLGA particles (BUD 100F) wassynthesized via the addition of a fluorescent agent.

Budesonide-PLGA [Poly(D,L-lactide-co-glycolide) ester terminated,lactide:glycolide 75:25, Mw 76,000-115,000, Sigma Aldrich]microparticles were synthesized using a continuous microfluidicdrug-PLGA droplet generation method, shown in FIG. 51. The set-up 600includes: pressurized vessel 602 containing the Water/PVA mixture asaqueous stream, 30 ml pressurized vessel 604 containing budesonide andPLGA dissolved in DCM, pressure pumps 606 equipped with flow ratesensors for transferring aqueous and organic phases to the chip 608, onereagent 100 μm hydrophilic glass 3D flow-focusing microfluidic glasschip 608 and customized holder—see the magnified view of the channelconfiguration in the chip 608 in the bottom-left of FIG. 51, Siliconizedglass stirred vessel 610 for collecting synthesized microparticles andsolvent evaporation, and PC with software 612 for controlling pumps 606with digital microscope interface for viewing and monitoring the dropletformation process.

The one reagent glass 3D flow-focusing microfluidic chip 608 withhydrophilic surface and 100 μm deep channels was used, followed by asolvent extraction step. Two partially miscible solvents includingdichloromethane and water were used as drug solvent/carrier and dropletscarrier phases, respectively. Budesonide (75, 100, and 125 mg/ml) and 1%w/v PLGA were dissolved in DCM as an organic fluid. 2% w/v PVA indouble-distilled water was used as an aqueous/carrier phase for dropletgeneration. All fluids passed through a 0.2 μm pore microfilter beforedroplet production. To generate fluorescence-sensitive budesonide-PLGAparticles, 0.3% w/v of PLGA-SH (LG 50:50, PolySciTech) and 20 μl ofAlexa Flour 647 C2 Maleimide dye (Invitrogen) was also added to thebudesonide-PLGA solution.

The microfluidic system set-up 600 includes two pressure pumps 606equipped with in-line flow rate sensors to monitor and control thestreams flow rates. Two flow rate sensors, 30-1000 μl/min and 1-50μl/min, were employed in the organic line and aqueous line,respectively. An air compressor (not shown) provided the supply pressurefor the pressure pumps 606 at 400 KPa working pressure. The pumps 606were connected to 30/400 ml and 30 ml volume remote pressure chambers602, 604 placed on magnetic stirrer for continuous mixing and deliveringof PVA in water and DCM-PLGA-Budesonide solution to the chip 608 with 10μl/min aqueous/carrier rate and 1.35 μl/min organic/drug-PLGA solutionsrate, respectively. The particle synthesis process was continuouslycontinued to reach 500 mg of particles while the DCM solvent wasevaporating/by connecting the particle's collection siliconized stirredvessel to very mild vacuum pressure (about 650 Torr). Three formulationsof budesonide-PLGA particles was synthesized with 75, 100, and 125 mg/mlconcentration of budesonide, denoted by BUD75, BUD100, and BUD125,respectively. Additionally, 100 mg/ml concentration of fluorescentbudesonide-PLGA particles (BUD 100F) was synthesized via addition ofAlexa Flour 647 C2 Maleimide as described.

FIG. 52 shows the morphological characteristics of the synthesized drugparticles for the different formulations exhibit budesonide encapsulatedinto PLGA microspheres with experimentally measured size (diameter)distribution of 35.1±5.2, 43.0±5.6, 56.9±5.5, and 42.8±3.9 μm,encapsulation efficiency of 65.3±2.1, 59.3±1.5, 45.3±1.5, and 61.3±1.5percent, and drug loading of 57.3±2.1, 54.5±1.5, 42.6±1.5, and 54.8±1.5percent for BUD 75, BUD 100, BUD 125, and BUD 100F, respectively(mean±SD, n=80-100 particles for each formulation).

The size of the prepared formulations for the drug-loaded particles (BUD75, BUD 100, BUD 125, and BUD 100F) was measured for an average of80-100 particles. A digital camera equipped with an optical microscopeused to visualize the particles, and counted by advanced image analysissoftware. About 9-11 mg of microparticles (MPs) in 3 replicates weresuspended and dissolved in 0.5 ml of acetonitrile by vortexing for 5min. Then, 500 μl of the solution with 5-fold dilution were prepared anddrug concentration in the replicates was measured using HPLC analysis(High Performance Liquid Chromatography) described below.

The obtained HPLC data were used to calculate drug loading andencapsulation efficacy parameters reported in FIG. 53, where Drugloading (%)=[mass of budesonide (mg) in MPs]/[mass of MPs (mg)]×100, andEncapsulation efficiency (%)=[mass of budesonide (mg) inMPs]/[theoretical mass of budesonide (mg) added initially]×100.

Budesonide kinetic release studies were analyzed using High-PerformanceLiquid Chromatography (HPLC). A 1260 Infinity II HPLC system equippedwith a 1260 quaternary pump, 1260 Hip ALS autosampler, 1290 thermostat,1260 TCC control module, and 1260 diode array detector. Data processingand analysis was performed using software. Budesonide chromatographicisocratic separation was carried out on an Agilent 4.6×150 mm ZorbaxEclipse XDB C-18 analytical column with 5 μm particles, maintained at30° C. The optimized mobile phase consisted of 20 mM dipotassiumphosphate buffer (pH 3.00 adjusted with phosphoric acid) andacetonitrile [30:70 (v/v)] at a flow rate of 1.00 mL/min over a 5 minrun time. The injection volume was 5 and the selected ultraviolet (UV)detection wavelength was 244 nm at a bandwidth of 4.0, no referencewavelength, and an acquisition rate of 40 Hz.

Drug release occurs through polymeric membrane erosion, allowing thedrug to diffuse out from the dialysis membrane. The in vitro releasekinetics of budesonide from the PLGA particles in a biorelevant fluid,phosphate-buffered saline (PBS), were analyzed using High-PerformanceLiquid Chromatography. The in vitro release of budesonide frommicroparticles was performed using a horizontal shaker with 200 rpmspeed at 37° C. Three to 5 milligrams of budesonide loadedmicroparticles were added to 1 ml phosphate buffered saline (PBS pH 7.4(1×)) with 0.1% Tween 20. Experiments were performed at 37° and sampleswere taken at 2, 4, 6 h, and then daily up to 7 days of release. Bufferwere refreshed at different time intervals and the drug content wasanalyzed using HPLC analysis of 500 μl of supernatant solution asdescribed via High-Performance Liquid Chromatography analysis. Notably,the release profile of encapsulated budesonide demonstrated an initialburst release followed by linear drug release up to approximately 40%across all the formulations over 7 days of incubation in PBS at 37° C.,as illustrated in FIG. 54.

The needle surfaces/tips of kirigami stents were loaded by pipetting 20μl of the BUD 100F particle solution two times per needle with a 5 hinterval for drying at room temperature. FIG. 55 shows the coatedkirigami stent and the magnified view of a needle surface/tip taken by afluorescence microscope, showing consistent deposition of a uniformbudesonide-PLGA microparticles layer onto the stent surface. Threeesophageal kirigami stents with drug-loaded polymeric particles weredelivered in vivo to the middle and distal esophagus of a large animalmodel (three Yorkshire pigs), and deposited drug particles viacircumferential injections.

To evaluate the ability of kirigami stents, loaded with thebudesonide-PLGA microparticles, to achieve long-term delivery, weadministered them to a large animal model (three Yorkshire pigs). Thedetails of delivery, deployment and removal of the stents were the sameas fluorescent particle-loaded stents previously described. The threeanimals were euthanized at three different time points: 1 day, 3 daysand 7 days after deployment/removal in compliance with the AVMAGuidelines on Euthanasia. Endoscopic evaluation of the esophagus overthe course of the study was performed to further explore the esophagusand ensure the absence of any ulceration or injury. The esophagi ofthree pigs were harvested and 8 mm diameter biopsies were used to takebiopsies at least seven needle penetration sites per retrievedesophagus. The penetration sites were recognized by using an IVISSpectrum in vivo imaging system. Note that the drug-loaded particles(BUD 100F) were fluorescence-sensitive due to incorporation of AlexaFlour 647 C2 Maleimide. The biopsies were then frozen until extraction.Budesonide was extracted from esophageal tissue by placing each biopsyin 500 μl of 5% BSA in PBS and homogenizing two times by 6500 rpm for 30seconds. A 100 μl fraction of the homogenate was collected. 50 μl of 5μg/ml hydrocortisone in acetonitrile and 1 mL ethyl acetate was addedfor budesonide extraction. These samples were vortex and centrifuged forten minutes at 13000 rpm. Following centrifugation, the supernatant wasevaporated to dryness. Samples were reconstituted in 300 μl acetonitrileand 200 μl of the reconstitute were pipetted into a 96-well platecontaining 200 μl of Nanopure water and used for ultraperformance liquidchromatography—tandem mass spectrometry (UPLC-MS/MS) analysis.

The esophagi was analyzed using ultraperformance liquidchromatography-tandem mass spectrometry (UPLC-MS/MS). The analysis wasperformed on a Waters ACQUITY UPLC- I-Class System aligned with a WatersXevo-TQ-S mass spectrometer. Liquid chromatographic separation wasperformed on an ACQUITY UPLC Charged Surface Hybrid C18 (50 mm×2.1 mm,1.7-μm particle size) column at 50° C. The mobile phase consisted ofaqueous 0.1% formic acid and 10 mM ammonium formate solution (mobilephase A) and an acetonitrile: 10 mM ammonium formate and 0.1% formicacid solution [95:5 (v/v)] (mobile phase B). The mobile phase had acontinuous flow rate of 0.6 ml/min using a time and solvent gradientcomposition. The initial composition (100% mobile phase A) was held for1 min, after which the composition was changed linearly to 50% mobilephase A over the next 0.25 min. At 1.5 min, the composition was 20%mobile phase A, and at 2.5 min, the composition was 0% mobile phase A,which was held constant until 3 min. The composition returned to 100%mobile phase A at 3.25 min and was held at this composition untilcompletion of the run, ending at 4 min, where it remained for columnequilibration. The total run time was 4 min, and sample injection volumewas 2.5 μl. The mass spectrometer was operated in the multiple reactionmonitoring (MRM) mode. Sample introduction and ionization was byelectrospray ionization (ESI) in the positive ionization mode. MassLynx4.1 software was used for data acquisition and analysis. Stock solutionsof budesonide and internal standard hydrocortisone were prepared inmethanol at a concentration of 500 μg/ml. A twelve-point calibrationcurve was prepared in methanol ranging from 1 to 5000 ng/ml.

The concentrations of budesonide delivered using the injectable stentsare reported in FIG. 56. The data indicates that budesonide could bedetected up to 0.09±0.02 μg/g per mass of tissue even after 7 days ofthe delivery, enabling sustained local delivery of budesonide andsupporting the potential for this controlled drug releasing system todeliver drug agents to the tubular segments of GI tract.

Discussion.

In summary, given the importance of innovative device development, aclass of drug releasing systems has been developed which are capable ofmultipoint injecting drug depots in the tubular mucosa of the GI tractsuch as the esophagus, enables sustained local drug delivery.Implementations of such a system were developed by: (i) design, FEmodeling, and prototyping a kirigami-based stent platform andcharacterize the mechanics for robust deployment, multi-point injection,and safe removal in the tubular mucosa of the GI tract, and (ii) in vivoevaluation of the capacity to deposit drug-loaded polymeric particlesfor extended release using a large animal model. To develop the kirigamistent, first, buckling-induced kirigami surfaces were engineered toundergo a shape transformation from flat surfaces to 3D texturedsurfaces with popped-up needles. By turning kirigami surfaces tocylindrical kirigami skins, a systematic study was presented throughcombining FE simulations and experiments to investigate the effect ofkirigami mesostructure (needle length and thickness) on the mechanicalresponse of kirigami shells. Next, a fluid-powered elastomeric actuatorwas employed to generate linear output motion using a simple controlinput (i.e., pressurization of a working fluid) to trigger the kirigamishell for injection. By combining kirigami design principles and thepneumatic soft actuator a new way to deliver drug depots locally isprovided and can be used to administer other APIs. Altogether, thisdesign of injectable kirigami stent offers a unique mechanism with arange of advantages: (i) can be applied to various length-scales to bematched with the size of the target tubular compartments of the GI tractand airways; (ii) be able to rapidly deploy by more than 50% radialexpansion and release therapeutics into submucosa throughcircumferential injections, and (iii) shape recovery to the originalflat configuration by releasing the actuator pressure for safe removal.

Plasma surface treatment that activates the plastic kirigami surfacesand results in the creation of hydrophilic surfaces, and laser engravingthe needle surfaces to increase surface area were used as twopost-treatment techniques to improve adhesion bond between the coatinglayer (drug-particle solution) and kirigami stents needles thatconsequently enhance drug loading capacity. However, some drug particlesmay be lost by washing off the stent during delivery. Further studies onvarious polymeric or plastic surfaces to make the kirigami shell withenhanced drug loading capacity as well as polymeric sacrificial layersto protect the drug-coated particles, can be performed to further boostdrug loading capacity and protected delivery without losing drugparticles that finally leads to improved local drug delivery.Introducing a sheath will also protect the stent during delivery andeliminate the use of a separate introducer for facile delivery. Otherdesigns including bi-material kirigami surfaces that includes plastichinges to provide out of plane popping motion and insoluble drug-loadedneedle tips for injection and deposit drug depots by dissolution intothe mucosa could improve delivery performance, and reduce the risk oftissue inflammation, and safe removal. These technologies can be furtherimproved through further in vivo testing of injectable kirigami stentswith the aforementioned improved designs and evaluation sustainedrelease within a target therapeutic range across different drugsdepending on the target application sites. Another design ofkirigami-based stents includes a design in which the kirigami spikes actas actuators to pop out and expose the attached small hypodermic needlesfor insertion. The hypodermic needles are connected via microchannels tothe space inside the actuator as a drug reservoir to transfer liquidtherapeutics.

While various spatial and directional terms, such as top, bottom, lower,mid, lateral, horizontal, vertical, front, and the like may be used todescribe examples of the present disclosure, it is understood that suchterms are merely used with respect to the orientations shown in thedrawings. The orientations may be inverted, rotated, or otherwisechanged, such that an upper portion is a lower portion, and vice versa,horizontal becomes vertical, and the like.

Within this specification, embodiments have been described in a waywhich enables a clear and concise specification to be written, but it isintended and will be appreciated that embodiments may be variouslycombined or separated without parting from the invention. For example,it will be appreciated that all preferred features described herein areapplicable to all aspects of the invention described herein.

Thus, while the invention has been described in connection withparticular embodiments and examples, the invention is not necessarily solimited, and that numerous other embodiments, examples, uses,modifications and departures from the embodiments, examples and uses areintended to be encompassed by the claims attached hereto. The entiredisclosure of each patent and publication cited herein is incorporatedby reference, as if each such patent or publication were individuallyincorporated by reference herein.

Various features and advantages of the invention are set forth in thefollowing claims.

What is claimed is:
 1. A stent for treating submucosal tissue of asubject, the stent comprising: a tubular body extending along a centralaxis and configured to move between a retracted position and anelongated position; and a plurality of projections formed into thetubular body, each projection forming a cutting edge to piercesubmucosal tissue within the gastrointestinal tract or trachea, whereineach projection among the plurality of projections is configured tochange orientation relative to the central axis when the tubular bodymoves between the retracted position and the elongated position.
 2. Thestent of claim 1, wherein when the tubular body is in the retractedposition, the plurality of projections form a cylindrical outer surfaceof the tubular body, and wherein when the tubular body is in theelongated position, the plurality of projections extend radially outwardfrom the tubular body into a deployed position to pierce the submucosaltissue proximate to the tubular body.
 3. The stent of claim 1, whereinthe projections define a needle angle between about 1 degrees and about90 degrees relative to the central axis when the projections are in adeployed position.
 4. The stent of claim 1, wherein the projections aretriangular-shaped, with a first edge and a second edge defining thecutting edge, and a base of the triangular-shaped projections definingan uncut portion of the tubular body.
 5. The stent of claim 1, whereinthe elongated position of the tubular body defines an elongated lengththat is between about 1% and about 100% greater than an initial lengthof the tubular body in the retracted position.
 6. The stent of claim 1,wherein the plurality of projections are formed by a pattern ofinterconnected cuts into the tubular body.
 7. The stent of claim 1,wherein the plurality of projections are circumferentially arrangedaround the tubular body.
 8. The stent of claim 1, wherein at least aportion of the stent is coated with a therapeutic agent.
 9. A stentsystem for treating a submucosal tissue of a subject, the systemcomprising: a tubular body extending along a central axis to form alumen within the tubular body, an actuator received within the lumen andconfigured to move the tubular body between a retracted position and anelongated position; and a pattern of a plurality of cuts formed alongthe tubular body and extending through the tubular body to the lumen,wherein the pattern of the plurality of cuts deploy into a plurality ofinterconnected projections that are configured to extend radially awayfrom the tubular body relative to the central axis to engage asubmucosal tissue within the gastrointestinal tract or trachea of asubject when the tubular body is moved towards the elongated position.10. The stent of claim 9, wherein when the tubular body is in theretracted position, the plurality of projections form a cylindricalouter surface of the tubular body.
 11. The stent of claim 9, wherein theprojections define a needle angle between about 1 degrees and about 90degrees relative to the central axis when the projection is in adeployed position.
 12. The stent of claim 9, wherein the projections aretriangular-shaped, with a first edge and a second edge defining acutting edge, and a base of the triangular-shaped projections definingan uncut portion of the tubular body.
 13. The stent of claim 9, whereinthe actuator is configured to elongate the tubular body to an elongatedlength that is between about 1% and about 100% greater than an initiallength of the tubular body in the retracted position.
 14. The stent ofclaim 9, wherein the actuator is a pneumatic actuator including anactuator body having an interior cavity and an inlet port, wherein theinlet port is configured to be in fluid communication with a pressurizedfluid source to provide pressurized fluid to the interior cavity. 15.The stent of claim 14, wherein the pneumatic actuator comprises anelastomeric material.
 16. The stent of claim 14, wherein the actuatorbody includes a fiber reinforcement extending along at least a portionof the length of the actuator body.
 17. The stent of claim 16, whereinthe fiber reinforcement includes strands of fibers arranged in a helicalpattern.
 18. A method of inserting a stent into a gastrointestinal tractor trachea a subject, the method comprising: positioning a stent to atarget tissue site within a gastrointestinal tract or trachea, the stenthaving a tubular body extending along a central axis to form a lumenwithin the tubular body, pressurizing an actuator received within thelumen to move the tubular body from a retracted position to an elongatedposition, wherein a surface of the tubular body includes a pattern of aplurality of cuts configured to deploy into a plurality ofinterconnected projections as the tubular body is moved into theelongated position to engage the target tissue site of the subject. 19.The method of claim 18, wherein the projections are coated in atherapeutic agent such that the therapeutic agent is delivered to thesubject when the projections engage the target tissue site.
 20. Themethod of claim 19, wherein the stent is inserted in a first, insertiondirection, and upon moving the tubular body into the elongated position,moving the stent in a second direction opposite the first direction todrive the projections into the target tissue site.